KR950000671A - Heteroatom-containing Ligands and Metal Complexes thereof - Google Patents

Heteroatom-containing Ligands and Metal Complexes thereof Download PDF

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KR950000671A
KR950000671A KR1019940013318A KR19940013318A KR950000671A KR 950000671 A KR950000671 A KR 950000671A KR 1019940013318 A KR1019940013318 A KR 1019940013318A KR 19940013318 A KR19940013318 A KR 19940013318A KR 950000671 A KR950000671 A KR 950000671A
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nitro
imidazol
oxa
tetramethyl
dioxime
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라마링감 콘데어디어
라주 나타라잔
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니콜라스 피.말라테스티닉
브리스톨-마이어즈 스퀴브 캄파니
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/62—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with triarylmethyl radicals attached to ring nitrogen atoms
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/70—Nitro radicals
    • C07D307/71—Nitro radicals attached in position 5
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    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
    • C07C251/32—Oximes
    • C07C251/34—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C251/36—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/38—Oximes with oxygen atoms of oxyimino groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with the carbon atoms of the oxyimino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Abstract

헤테로원자－포함 가교를 함유하는 신규 화합물 및 이들 화합물과 금속과의 신규한 착화합물이 기술되어 있다. 신규 화합물 및 착화합물은 진단 및 치료 방법에 유용하다.Novel compounds containing heteroatom-containing crosslinks and novel complexes of these compounds with metals are described. New compounds and complexes are useful for diagnostic and therapeutic methods.

Description

헤테로원자－포함 리간드 및 이의 금속 착화합물Heteroatom-containing ligands and metal complexes thereof

본 내용은 요부공개 건이므로 전문내용을 수록하지 않았음Since this is an open matter, no full text was included.

Claims (25)

하기 일반식(Ia),(Ib) 또는 (Ic)의 화합물.Compounds of the following general formulas (Ia), (Ib) or (Ic). 상기 식에서, Q는 그룹 －(C(RR))m1－Y1－(C(RR))m2－(Y2－(C(RR)m|3)n－(여기서,Y1및 Y2는 각각 독립적으로 －NR－, －O－, －S－, －SO－, －SO1－ 또는 －Se－이고; n은 0 또는 1에서 선택된 정수이고 ; m1, m2 및 m3는 0 내지 4로부터 독립적으로 선택된 정수이며, 단 m1 및 m2의 합은 0보다 크다)이고; 모든 R 및 R*그룹은 독립적으로, (ⅰ) R2; (ⅱ) 할로겐; (ⅲ) －OR2; (ⅳ) －C(O)－OR2; (ⅴ) －C(O－N(R2)2; (ⅵ) －N(R2)2; (ⅶ) －알킬－C(O)－OR2; (ⅷ) －알킬－C(O)－N(R2)2; (ⅸ) －알킬－N(R2)2; (ⅹ) －아릴－C(O)－OR2; (xi) －아릴－C(O)－N(R|2)2; (xii) －아릴－N(R2)2; (xiii) 아실 ; (xiv) 아실옥시 ; (xv) 헤테로사이클로 ; (xvi) 하이드록시알킬; (xvii) －SO2－R2; (xviii) －알킬－SO2－R2; (xix) －(A)p－R3 Wherein Q is a group-(C (RR)) m 1 -Y 1- (C (RR)) m 2- (Y 2- (C (RR) m | 3 ) n- (where Y 1 and Y 2 are each independently -NR-, -O-, -S-, -SO-, -SO 1 -or -Se-; n is an integer selected from 0 or 1; m1, m2 and m3 are 0 to 4 An integer independently selected from the sum of m1 and m2, provided that the sum of m1 and m2 is greater than 0); and all R and R * groups are independently: (i) R 2 ; (ii) halogen; (iii) -OR 2 ; ) -C (O) -OR 2 ; (ⅴ) -C (O-N (R 2 ) 2 ; (ⅵ) -N (R 2 ) 2 ; (ⅶ) -alkyl-C (O) -OR 2 ; (ⅷ) - alkyl, -C (O) -N (R 2 ) 2; (ⅸ) - alkyl, -N (R 2) 2; ( ⅹ) - aryl -C (O) -OR 2; ( xi) - aryl -C (O) -N (R | 2 ) 2 ; (xii) -aryl-N (R 2 ) 2 ; (xiii) acyl; (xiv) acyloxy; (xv) heterocyclo; (xvi) hydroxyalkyl (xvii) -SO 2 -R 2 ; (xviii) -alkyl-SO 2 -R 2 ; (xix)-(A) p-R 3 (여기서, A는 연결 그룹이고, p는 0 또는 양의 정수이며, R3은 생체활성 잔기이다)이거나; 또는Wherein A is a linking group, p is 0 or a positive integer and R 3 is a bioactive moiety; or (XX)두개의 R그룹, 또는 R그룹 하나와 R*그룹 하나는, 이들이 결합된 원자 하나 이상과 함께, 비치환되거나 또는 상기 그룹(i) 내지 (xix) 중에서 선택된 그룹 하나 이상으로 치환될 수 있는, 포화 또는 불포화, 스피로 또는 융합된, 카보사이클릭 또는 헤테로사이클릭 환을 형성하는데, 단 R그룹을 포함하는 탄소 원자는 하나 초과의 헤테로원자에 직접 결합하지 않으며 ; R1은 수소 ; 티올 보호 그룹 ; 또는 상기 정의된 그룹 －(A)p－R3이고 ; R2는 독립적으로 수소, 알킬, 알케닐, 알키닐 또는 아릴이다.(XX) two R groups, or one R group and one R * group, together with one or more atoms to which they are attached, may be unsubstituted or substituted with one or more groups selected from groups (i) to (xix) Form a carbocyclic or heterocyclic ring which is saturated or unsaturated, spiro or fused, provided that a carbon atom comprising an R group does not directly bond to more than one heteroatom; R 1 is hydrogen; Thiol protecting group; Or the group-(A) p -R 3 as defined above; R 2 is independently hydrogen, alkyl, alkenyl, alkynyl or aryl. 제 1 항에 있어서, 화합물이 그룹(xx)를 함유하는 경우, 이 그룹은 두개의 R그룹을 함유하여 이들이 결합된 원자 하나 이상과 함께, 비치환되거나 또는 그룹(i) 내지 (xix)중에서 선택된 그룹 하나 이상으로 치환될 수 있는, 포화 또는 불포화 스피로 또는 융합된, 카보사이클릭 또는 헤테로사이클릭 환을 형성하는 화합물.The compound of claim 1, wherein the compound contains a group (xx), which contains two R groups, together with one or more atoms to which they are attached, unsubstituted or selected from groups (i) to (xix). Compounds that form carbocyclic or heterocyclic rings, saturated or unsaturated spiro or fused, which may be substituted with one or more groups. 제 1 항에 있어서, 하기 일반식(Ia´)의 화합물.A compound of formula (Ia ') according to claim 1. 상기 식에서, Z1및 Z2는 R*그룹이고, Z3는 R그룹이며, 또한 Z1, Z2및 Z3그룹 중 하나, 둘 또는 모두는 －(A)p－R3그룹이다.Wherein Z 1 and Z 2 are R * groups, Z 3 is an R group, and one, two or both of the Z 1 , Z 2 and Z 3 groups are — (A) p —R 3 groups. 제 3 항에 있어서, Y1이 －NR－ 또는 －O－인 화합물.4. A compound according to claim 3, wherein Y 1 is -NR- or -O-. 제 4 항에 있어서, Y1이 －O－인 화합물The compound of claim 4, wherein Y 1 is —O—. 제 3 항에 있어서, R3가 저산소중－편재 잔기인 화합물.4. The compound of claim 3, wherein R 3 is a hypoxic-localized residue. 제 6 항에 있어서, (A)－P－R3가 아닌 R 또는 R*그룹이 수소 또는 알킬 그룹인 화합물.A compound according to claim 6, wherein R or R * groups other than (A) -P-R 3 are hydrogen or an alkyl group. 제 6 항에 있어서, R3가 니트로이미다졸 또는 니트로푸란 그룹인 화합물.The compound of claim 6, wherein R 3 is a nitroimidazole or nitrofuran group. 제 1 항에 있어서, 3,3,5,9,9－펜타메틸－4,5,8－트리아자운데칸－2,10－디온 디옥심 ; 11－(2－니트로－1H－이미다졸－1－일)－3,3,5,9,9－펜타메틸－4,5,8－트리아자운데칸－2,10－디온 디옥심 ; 12－(2－니트로－1H－이미다졸－1－일)－3,3,5,9,9－펜타메틸－4,5,8－트리아자운데칸－2,10－디온 디옥심 ; 1－(2－니트로－1H－이미다졸－1－일)－4,4,6,10,10－펜타메틸－5,6,9－트리아자도데칸－3,11－디온 디옥심 ; 3,3,9,9－테트라메틸－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 11－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－테트라메틸－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 1－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－테트라메틸－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 12－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－테트라메틸－7－옥사－4,8－디아자－2,10－도데칸디온 디옥심 ; 12－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－테트라메틸－5－옥사－4,8－디아자－2,10－도데칸디온 디옥심 ; 1,13－비스(2－니트로－1H－이미다졸－1－일)－4,4,10,10－테트라메틸－6－옥사－5,9－디아자－3,11－트리데칸디온 디옥심 ; 1－[[2－니트로－1H－이미다졸－1－일)아세틸]아미노]－3,3,9,9－테트라메틸－5－옥사－4,8－디아자－2,10－운데칸디온 디옥심 ; 1－[(2－하이드록시－3(2－니트로－1H－이미다졸－1－일)프로폭시]－3,3,9,9－테트라메틸－옥사－4,8－디아자－2,10－운데칸디온 디옥심 ; 1－하이드록시－3,3,9,9－테트라메틸－12－(2－니트로－1H－이미다졸－1－일)－7－옥사－4,8－디아자도데칸－2,10－디온 디옥심 ; 3,3,9,9－테트라메틸－6－[(2니트로－1H－이미다졸－1－일)메틸]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 4,4,10,10－테트라메틸－1,13－비스(2－니트로－1H－이미다졸－1－일)－7－[(2-니트로－1H－이미다졸－1－일)메틸]－6－옥사－5,9－디아자트리데칸－3,11－디온 디옥심 ; 1,13－비스(2－니트로－1H－이미다졸－1－일)－4,4,10,10－테트라메틸－6－옥사－7－(하이드록시메틸－5,9－디아자－3,11－도데칸디온 디옥심 ; 12－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－테트라메틸－6－(하이드록시메틸)－7－옥사－4,8－디아자－2,10－도데칸디온 디옥심 ; 3,3,9,9－테트라메틸－6－[[3－(2－니트로－1H－이미다졸－1－일)프로폭시]메틸]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 1－에톡시－3,3,9,9－테트라메틸－12－(2－니트로－1H－이미다졸－1－일)－6－[(2－니트로이미다졸－1－일)메틸]7옥사－4,8－디아자도데칸－2,10－디온 디옥심 ; 3,3,9,9－테트라메틸－1－에톡시－6－[(2－니트로－1H－이미다졸－1－일)메틸]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 4,4,10,10－테트라메틸－7－[(2－니트로－1H－이미다졸－1－일)메틸]－6－옥사－5,9－디아자트리데칸－3,11－디온 디옥심 ; 4,4,10,10 테트라메틸-7-[(2-니트로-1H-이미다졸-1-일)메틸]-8-옥사-5.9-디아자펜타데칸-3,11-디온 디옥심 ; 5,5,11,11－테트라메틸－1－(5－니트로－2－푸릴)－2,9－디옥사－6,10－디아자테트라데칸－4,12－디온 디옥심 ; 5,5,11,11－테트라메틸－1－(5－니트로－2－푸릴)－2,7－디옥사－6,10－디아자테트라데칸－4,12－디온 디옥심 ; 3,3,9,9－테트라메틸－1－[[(5－니트로－2－푸릴)카보닐]아미노]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 및 3,3,6,9,9－펜타메틸－5－옥사－4,8－디아자－4,8－디아자운데칸－2,10－디온 디옥심으로 이루어진 그룹 중에서 선택되는 화합물.3,3,5,9,9-pentamethyl-4,5,8-triazadecane-2,10-dione dioxime; 11- (2-nitro-1H-imidazol-1-yl) -3,3,5,9,9-pentamethyl-4,5,8-triazadecane-2,10-dione dioxime; 12- (2-nitro-1H-imidazol-1-yl) -3,3,5,9,9-pentamethyl-4,5,8-triazadecane-2,10-dione dioxime; 1- (2-nitro-1H-imidazol-1-yl) -4,4,6,10,10-pentamethyl-5,6,9-triazadodecane-3,11-dione dioxime; 3,3,9,9-tetramethyl-5-oxa-4,8-diazanedecane-2,10-dione dioxime; 11- (2-nitro-1H-imidazol-1-yl) -3,3,9,9-tetramethyl-5-oxa-4,8-diazadecane-2,10-dione dioxime; 1- (2-nitro-1H-imidazol-1-yl) -3,3,9,9-tetramethyl-5-oxa-4,8-diazadecane-2,10-dione dioxime; 12- (2-nitro-1H-imidazol-1-yl) -3,3,9,9-tetramethyl-7-oxa-4,8-diaza-2,10-dodecanedioone dioxime; 12- (2-nitro-1H-imidazol-1-yl) -3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10-dodecanedione dioxime; 1,13-bis (2-nitro-1H-imidazol-1-yl) -4,4,10,10-tetramethyl-6-oxa-5,9-diaza-3,11-tridecanedione di Oxime; 1-[[2-nitro-1H-imidazol-1-yl) acetyl] amino] -3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10-undecane Dion Dioxime; 1-[(2-hydroxy-3 (2-nitro-1H-imidazol-1-yl) propoxy] -3,3,9,9-tetramethyl-oxa-4,8-diaza-2, 10-undecandione dioxime; 1-hydroxy-3,3,9,9-tetramethyl-12- (2-nitro-1H-imidazol-1-yl) -7-oxa-4,8-dia Zadodecane-2,10-dione dioxime; 3,3,9,9-tetramethyl-6-[(2nitro-1H-imidazol-1-yl) methyl] -5-oxa-4,8-dia Zaoundecan-2,10-dione dioxime; 4,4,10,10-tetramethyl-1,13-bis (2-nitro-1H-imidazol-1-yl) -7-[(2-nitro- 1H-imidazol-1-yl) methyl] -6-oxa-5,9-diazatridecane-3,11-dione dioxime; 1,13-bis (2-nitro-1H-imidazole-1- Japanese) -4,4,10,10-tetramethyl-6-oxa-7- (hydroxymethyl-5,9-diaza-3,11-dodecanedioone dioxime; 12- (2-nitro-1H -Imidazol-1-yl) -3,3,9,9-tetramethyl-6- (hydr Dimethyl) -7-oxa-4,8-diaza-2,10-dodecanedioone dioxime; 3,3,9,9-tetramethyl-6-[[3- (2-nitro-1H-imid) Dazol-1-yl) propoxy] methyl] -5-oxa-4,8-diazanedecane-2,10-dione dioxime; 1-ethoxy-3,3,9,9-tetramethyl-12- (2-nitro-1H-imidazol-1-yl) -6-[(2-nitroimidazole-1-yl) methyl] 7oxa-4,8-diazadodecane-2,10-dione dioxime; 3,3,9,9-tetramethyl-1-ethoxy-6-[(2-nitro-1H-imidazol-1-yl) methyl] -5-oxa-4,8-diazadecane-2, 10-dione dioxime: 4,4,10,10-tetramethyl-7-[(2-nitro-1H-imidazol-1-yl) methyl] -6-oxa-5,9- diaztridecane- 3,11-dione dioxime; 4,4,10,10 tetramethyl-7-[(2-nitro-1H-imidazol-1-yl) methyl] -8-oxa-5.9-diazapentadecane-3 , 11-dione dioxime; 5,5,11,11-tetramethyl-1- (5-nitro-2-furyl) -2,9-diox -6,10- diazatetradecane-4,12- dione dioxime; 5,5,11,11-tetramethyl-l- (5-nitro-2-furyl) -2,7-dioxa-6, 10-diazatetradecane-4,12-dione dioxime; 3,3,9,9-tetramethyl-1-[[(5-nitro-2-furyl) carbonyl] amino] -5-oxa-4,8-diazadecane-2,10-dione dioxime; And 3,3,6,9,9-pentamethyl-5-oxa-4,8-diaza-4,8-diazadecane-2,10-dione dioxime. 제 1 항에 있어서, (R)－3,3,9,9－테트라메틸－6－[(2－니트로－1H－이미다졸－1－일)메틸]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 또는 (S)－3,3,9,9－테트라메틸－6－[(2－니트로－1H－이미다졸－1－일)메틸]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심인 화합물.(R) -3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl) methyl] -5-oxa-4,8-dia Zaoundecan-2,10-dione dioxime; Or (S) -3,3,9,9-tetramethyl-6-[(2-nitro-1H-imidazol-1-yl) methyl] -5-oxa-4,8-diazadecane-2, A compound which is 10-dione dioxime. 금속과 착화된 제 1 항의 화합물을 포함하는 착화합물.A complex comprising a compound of claim 1 complexed with a metal. 제11항에 있어서, 하기 일반식(Iacomplex) 또는 (Iccomplex) 의 착화물.The complex of Claim 11 whose general formula (Ia complex ) or (Ic complex ) is a complex. 상기 식에서, R 및 R*그룹은 제 1 항에서 정의된 바와 같고 ; M은 방사성, 또는 비충전 배위 부위에서 다른 보조－리간드(들) W1및/또는 W2를 임의로 가질 수 있는 비－방사성 금속이다.Wherein R and R * groups are as defined in claim 1; M is a non-radioactive metal which may optionally have other co-ligand (s) W 1 and / or W 2 at the radioactive or non-filling coordination site. 제12항에 있어서, 금속이 테크네튬 또는 레늄인 착화합물.The complex of claim 12, wherein the metal is technetium or rhenium. 제13항에 있어서, 하기 구조식의 착화합물.The complex of claim 13 wherein the complex is of the formula 상기 식에서, M1은 테크네튬이고, M2는 테크네튬 또는 레늄이며, R 또는 R*그룹 중 하나 이상은 －(A)p－R3이다.Wherein M 1 is technetium, M 2 is technetium or rhenium, and at least one of the R or R * groups is — (A) p—R 3 . 제11항에 있어서, 테크네튬이 하기 화합물로 이루어진 그룹 중에서 선택된 화합물과 착화된 착화합물 ; 3,3,5,9,9－펜타메틸－4,5,8－트리아자운데칸－2,10－디온 디옥심 ; 11－(2－니트로－1H－이미다졸－1－일)－3,3,5,9,9－펜타메틸－4,5,8－트리아자운데칸－2,10－디온 디옥심 ; 12－(2－니트로－1H－이미다졸－1－일)－3,3,5,9,9－펜타메틸－4,5,8－트리아자도데칸－2,10－디온 디옥심, 1－(2－니트로－1H－이미다졸－1－일)－3,3,5,9,9－펜타메틸－4,5,8－트리아자운데칸－2,10－디온 디옥심 ; 1－(2－니트로－1H－아미다졸－1－일)－4,4,6,10,10－펜타메틸－5,6,9－트리아자도데칸－3,11－디온 디옥심 ; 3,3,9,9－테트라메틸－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 11－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－테트라메틸－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 1－(2－니트로－1H－아미다졸－1－일)－3,3,9,9－테트라메틸－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 12－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－테트라메틸－7－옥사－4,8－디아자－2,10－도데칸 디온 디옥심 ; 12－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－테트라메틸－5－옥사－4,8－디아자－2,1－도데칸 디온 디옥심 ; 1,13－비스(2－니트로－1H－이미다졸－1－일)－4,4,10,10－테트라메틸－6－옥사－5,9－디아자－3,11－트리데칸디온 디옥심 ; 1－[[2－니트로－1H－이미다졸－1－일)아세틸]아미노]－3,3,9,9－테트라메틸－5－옥사－4,8－디아자－2,10－운데칸디온 디옥심 ; 1－[2－하이드록시－3－(2－니트로－1H－이미다졸－1－일)프로폭시]－3,3,9,9－테트라메틸－옥사－4,8－디아자－2,10－운데칸디온 디옥심 ; 1－하이드록시－3,3,9,9－테트라메틸－12－(2－니트로－1H－이미다졸－1－일)－7－옥사－4,8－디아자도데칸－2,10－디온 디옥심 ; 3,3,9,9－데트라메틸－6－[(2－니트로－1H－이미다졸－1－일)메틸]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 4,4,10,10－테트라메틸－1,13－비스(2－니트로－1H－이미다졸－1－일)－7－[(2－니트로－1H－일)메틸]－6－옥사－5,9－디아자트리데칸－3,11－디온 디옥심 ; 1,13－비스(2－니트로－1H－이미다졸－1－일)－4,4,10,10－테트라메틸－6－옥사－7－(하이드록시메틸)－5,9－디아자－3,11－도데칸디온 디옥심 ; 12－(2－니트로－1H－이미다졸－1－일)－3,3,9,9－데트라메틸－6－(하이드록시메틸)－7－옥사－4,8－디아자－2,10－도데칸디온 디옥심 ; 3,3,9,9－데트라메틸－6－[[3－(2－니트로－1H－이미다졸－1－일)프로폭시]메틸]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 1－에톡시－3,3,9,9－데트라메틸－12－(2－니트로－1H－이미다졸－1－일)－6－[(2－니트로이미다졸－1－일)메틸]－7－옥사－4,8－디아자도데칸－2,10－디온 디옥심 ; 3,3,9,9－데트라메틸－1－에톡시－6－[(2－니트로－1H－이미다졸－1－일)메틸]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 4,4,10,10－테트라메틸－7－[(2－니트로－1H－이미다졸－1－일)메틸]－6－옥사－5,9－디아자트리데칸－3,11－디온 디옥심 ; 4,4,10,10－테트라메틸－7－[(2－니트로－1H－이미다졸－1－일)메틸]－8－옥사－5,9－디아자펜타데칸－3,11－디온 디옥심 ; 5,5,11,11－테트라메틸－1－(5－니트로－2－푸릴)－2,9－디옥사－6,10－디아자테트라데칸－4,12－디온 디옥심 ; 5,5,11,11－테트라메틸－1－(5－니트로－2－푸릴)－2,7－디옥사－6,10－디아자테트라데칸－4,12－디온 디옥심 ; 3,3,9,9－테트라메틸－1－[[5－니트로－2－푸릴)카보닐]아미노]－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심 ; 및 3,3,6,9,9－펜타메틸－5－옥사－4,8－디아자운데칸－2,10－디온 디옥심.The complex of Claim 11, wherein the technetium is complexed with a compound selected from the group consisting of the following compounds; 3,3,5,9,9-pentamethyl-4,5,8-triazadecane-2,10-dione dioxime; 11- (2-nitro-1H-imidazol-1-yl) -3,3,5,9,9-pentamethyl-4,5,8-triazadecane-2,10-dione dioxime; 12- (2-nitro-1H-imidazol-1-yl) -3,3,5,9,9-pentamethyl-4,5,8-triazadodecane-2,10-dione dioxime, 1- (2-nitro-1H-imidazol-1-yl) -3,3,5,9,9-pentamethyl-4,5,8-triazadecane-2,10- dione dioxime; 1- (2-nitro-1H-amidazole-1-yl) -4,4,6,10,10-pentamethyl-5,6,9-triazadodecane-3,11-dione dioxime; 3,3,9,9-tetramethyl-5-oxa-4,8-diazanedecane-2,10-dione dioxime; 11- (2-nitro-1H-imidazol-1-yl) -3,3,9,9-tetramethyl-5-oxa-4,8-diazadecane-2,10-dione dioxime; 1- (2-nitro-1H-amidazole-1-yl) -3,3,9,9-tetramethyl-5-oxa-4,8-diazadecane-2,10-dione dioxime; 12- (2-nitro-1H-imidazol-1-yl) -3,3,9,9-tetramethyl-7-oxa-4,8-diaza-2,10-dodecane dione dioxime; 12- (2-nitro-1H-imidazol-1-yl) -3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,1-dodecane dione dioxime; 1,13-bis (2-nitro-1H-imidazol-1-yl) -4,4,10,10-tetramethyl-6-oxa-5,9-diaza-3,11-tridecanedione di Oxime; 1-[[2-nitro-1H-imidazol-1-yl) acetyl] amino] -3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10-undecane Dion Dioxime; 1- [2-hydroxy-3- (2-nitro-1H-imidazol-1-yl) propoxy] -3,3,9,9-tetramethyl-oxa-4,8-diaza-2, 10-undecandione dioxime; 1-hydroxy-3,3,9,9-tetramethyl-12- (2-nitro-1H-imidazol-1-yl) -7-oxa-4,8-diazadodecane-2,10-dione Dioxime; 3,3,9,9-detramethyl-6-[(2-nitro-1H-imidazol-1-yl) methyl] -5-oxa-4,8-diazadecane-2,10-dione di Oxime; 4,4,10,10-tetramethyl-1,13-bis (2-nitro-1H-imidazol-1-yl) -7-[(2-nitro-1H-yl) methyl] -6-oxa- 5,9- diaztridecane-3,11- dione dioxime; 1,13-bis (2-nitro-1H-imidazol-1-yl) -4,4,10,10-tetramethyl-6-oxa-7- (hydroxymethyl) -5,9-diaza- 3,11-dodecanedione dioxime; 12- (2-nitro-1H-imidazol-1-yl) -3,3,9,9-detramethyl-6- (hydroxymethyl) -7-oxa-4,8-diaza-2, 10-dodecanedione dioxime; 3,3,9,9-detramethyl-6-[[3- (2-nitro-1H-imidazol-1-yl) propoxy] methyl] -5-oxa-4,8-diazanedecane- 2,10- dione dioxime; 1-Ethoxy-3,3,9,9-detramethyl-12- (2-nitro-1H-imidazol-1-yl) -6-[(2-nitroimidazole-1-yl) methyl] -7-oxa-4,8-diazadodecane-2,10- dione dioxime; 3,3,9,9-detramethyl-1-ethoxy-6-[(2-nitro-1H-imidazol-1-yl) methyl] -5-oxa-4,8-diazadecane-2 , 10-dione dioxime; 4,4,10,10-tetramethyl-7-[(2-nitro-1H-imidazol-1-yl) methyl] -6-oxa-5,9- diaztridecane-3,11-dione di Oxime; 4,4,10,10-tetramethyl-7-[(2-nitro-1H-imidazol-1-yl) methyl] -8-oxa-5,9-diazapentadecane-3,11-dione di Oxime; 5,5,11,11-tetramethyl-1- (5-nitro-2-furyl) -2,9-dioxa-6,10-diazatetradecane-4,12-dione dioxime; 5,5,11,11-tetramethyl-1- (5-nitro-2-furyl) -2,7-dioxa-6,10-diazatetradecane-4,12-dione dioxime; 3,3,9,9-tetramethyl-1-[[5-nitro-2-furyl) carbonyl] amino] -5-oxa-4,8-diazadecane-2,10-dione dioxime; And 3,3,6,9,9-pentamethyl-5-oxa-4,8-diazanedecane-2,10-dione dioxime. 15항에 있어서, 옥소[(R)－6－(2－니트로－1H－이미다졸－1－일)메틸]－3,3,9,9－테트라메틸－5－옥사－4,8－디아자－2,10－운데칸디온－디옥시메이토](3－)－N,N´, N˝, N″′]테크네튬 －99mTc(V); 또는 옥소[(S)－6(2－니트로－1H－이미다졸－1－일)메틸]－3,3,9,9－테트라메틸－5－옥사－4,8－디아자－2,10－운데칸디온 디옥시메이토](3－)－N,N´, N˝, N″′]테크네이튬 －99mTc(V)인 착화합물.The method according to claim 15, wherein oxo [(R) -6- (2-nitro-1H-imidazol-1-yl) methyl] -3,3,9,9-tetramethyl-5-oxa-4,8-dia Purple-2,10-undecandione-dioxymeto] (3-)-N, N ', N', N "'] technetium -99 m Tc (V); Or oxo [(S) -6 (2-nitro-1H-imidazol-1-yl) methyl] -3,3,9,9-tetramethyl-5-oxa-4,8-diaza-2,10 -Undecanedione deoxymeto] (3-)-N, N ', N', N "'] technium-99 m Tc (V). 진단을 필요로 하는 대상에서 제11항의 착화합물을 투여하고 이를 영상화함을 특징으로 하는 진단 방법.A diagnostic method comprising administering and imaging a complex of claim 11 in a subject in need of diagnosis. 제17항에 있어서, 착화합물의 금속이 테크네튬인 방법.18. The method of claim 17, wherein the metal of the complex is technetium. 제17항에 있어서, 저산소증 조직을 대상에서 영상화하는 방법.The method of claim 17, wherein the hypoxic tissue is imaged in the subject. 질병의 치료를 필요로 하는 대상에서 제11항의 착화합물을 투여함을 특징으로 하는 질병의 치료 방법.A method for treating a disease, characterized by administering the complex of claim 11 to a subject in need thereof. 제20항에 있어서, 착화합물의 금속이 레늄인 방법.The method of claim 20, wherein the metal of the complex is rhenium. 제11항의 화합물 및 약제학적으로 허용되는 환원제를 포함하는 키트(kit)A kit comprising the compound of claim 11 and a pharmaceutically acceptable reducing agent 제22항에 있어서, 제 1 항의 화합물 및 약제학적으로 허용되는 환원제를 함유하는 단일 바이알을 포함하는 키트.The kit of claim 22 comprising a single vial containing the compound of claim 1 and a pharmaceutically acceptable reducing agent. 제22항에 있어서, 제 1 항의 화합물을 함유하는 제 1 바이알 및 약제학적으로 허용되는 환원제를 함유하는 제 2 바이알을 포함하는 키트.The kit of claim 22 comprising a first vial containing the compound of claim 1 and a second vial containing a pharmaceutically acceptable reducing agent. (i)(S)－(＋)－에피클로로하이드린 또는 (R)－(－)－에피클로로하이드린을 프탈이미드와 반응시켜 1－클로로－3－프탈이미도－2－프로판올의 입체 이성질체를 형성시키고 ; (ii)(i)의 생성물을 에폭사이드환－형성체와 접촉시켜 N－(2,3－에폭시프로필)프탈이미드의 입성 이성체를 수득하여 ; (iii)(ii)의 생성물을 염기 및 2－니트로이미다졸과 접촉시켜 2－[2－하이드록시－2－(니트로－1H－이미다졸－1－일)에틸]－1H－이소인돌－1,3(2H)－디온의 입체 이성체를 수득하고 ; (iv)(iii)의 생성물을 하이드라진, 이어서 염기디 3급 부틸 디카보네이트와 접촉시켜 α－[(t－Boc－아미노)메틸]－2－니트로－1H－이미다졸－1－에탄올의 입체이성체를 수득하여 ; (v)(iv)의 생성물을 N－하이드록시프탈이미드, 트리페닐포스핀 및 디에필아조 디카복실레이트와 접촉시켜 2－[1－[(t－Boc－아미노)메틸]－2－니트로－1H－이미다졸－1－일)에톡시]1H－이소인돌－1,3(2H)－디온의 입이성체를 수득하고 ; (vi)(v)의 생성물을 하이드라진과 접촉시켜 1－[2－아미녹시)－3－(t－Boc－아미노)프로필]－니트로－1H－이미다졸의 입성 이성체를 수득하고 ;(ⅶ)(vii)의 생성물을 탈보호시켜 1－[3－아미노-2-(아미녹시)프로필]-2-니트로-1H-이미다졸의 입성이성체를 수득하고; (viii) (ⅶ)의 생성물을 3급 아민의 존재하에서 3－클로로－3－메틸－2－니트로소부탄과 접촉시켜 제10항의 화합물을 수득하는 단계를 포함함을 특징으로 하여, 제10항의 화합물을 입체선택적으로 제조하는 방법.(i) (S)-(+)-Epichlorohydrin or (R)-(-)-Epichlorohydrin by reacting with phthalimide to give a steric conformation of 1-chloro-3-phthalimido-2-propanol To form isomers; (ii) contacting the product of (i) with an epoxide ring-former to obtain granular isomers of N- (2,3-epoxypropyl) phthalimide; (iii) The product of (ii) was contacted with a base and 2-nitroimidazole to give 2- [2-hydroxy-2- (nitro-1H-imidazol-1-yl) ethyl] -1H-isoindole-1. To obtain stereoisomers of 3 (2H) -dione; (iv) The product of (iii) is contacted with hydrazine followed by base di tert-butyl dicarbonate to give stereoisomers of α-[(t-Boc-amino) methyl] -2-nitro-1H-imidazole-1-ethanol To obtain; (v) The product of (iv) is contacted with N-hydroxyphthalimide, triphenylphosphine and diefilazo dicarboxylate to give 2- [1-[(t-Boc-amino) methyl] -2-nitro. Isomers of -1H-imidazol-1-yl) ethoxy] 1H-isoindole-1,3 (2H) -dione; (vi) The product of (v) was contacted with hydrazine to obtain granular isomers of 1- [2-aminooxy) -3- (t-Boc-amino) propyl] -nitro-1H-imidazole; deprotecting the product of (vii) to give the granules of 1- [3-amino-2- (aminooxy) propyl] -2-nitro-1H-imidazole; (viii) contacting the product of (iii) with 3-chloro-3-methyl-2-nitrosobutane in the presence of a tertiary amine to obtain the compound of claim 10; Method for stereoselectively preparing a compound. ※ 참고사항 : 최초출원 내용에 의하여 공개하는 것임.※ Note: The disclosure is based on the initial application.
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DE69409870T2 (en) 1998-12-10
JP3835831B2 (en) 2006-10-18
AU678001B2 (en) 1997-05-15
CA2125895C (en) 2000-03-14
ZA944201B (en) 1995-02-08
NO942231L (en) 1994-12-16
CZ295519B6 (en) 2005-08-17
US5741912A (en) 1998-04-21
KR100346795B1 (en) 2002-11-29
US5665329A (en) 1997-09-09
DK0629617T3 (en) 1998-10-07
US5627286A (en) 1997-05-06
NO305078B1 (en) 1999-03-29
PL303843A1 (en) 1994-12-27
RU94022254A (en) 1996-04-20
IL109925A (en) 2005-12-18
EP0629617B2 (en) 2007-09-26
US5608110A (en) 1997-03-04
FI942795A (en) 1994-12-16
DE69409870T3 (en) 2008-03-13
EP0629617B1 (en) 1998-04-29
FI942795A0 (en) 1994-06-13
CA2125895A1 (en) 1994-12-16
IL109925A0 (en) 1994-10-07
ES2115805T3 (en) 1998-07-01
CZ145594A3 (en) 1995-05-17
AU6467294A (en) 1994-12-22
CN1055685C (en) 2000-08-23
DE69409870D1 (en) 1998-06-04
CN1099388A (en) 1995-03-01
HU9401777D0 (en) 1994-09-28
EP0629617A1 (en) 1994-12-21
NO942231D0 (en) 1994-06-14
US5656254A (en) 1997-08-12
JPH0789922A (en) 1995-04-04

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